Synthesis of phenylamino propanediol alkylethers and intermediates obtained thereby



2,824,878 Ice Patented F 1958 1. 7 2 2,824,878 Thus, walkoxyme'thy l-B hydroxy fi-aryl alkyl ropionate (3') is obtained, t-ne hydrazide (4) of which, resulting SYNTHESIS OF PHENYLAMJNO PROPANEDIOL from the reaction with 'h'draziine 'h draft: in boiling a1- ALsEmfiERs 'INTERNIEDIATES cohol, is transformed init o a 5'-ary l 4-alkoxy metliyl 2- T D THEREBY 5 oxazolidone (5) upon treatment with nitrous acid in'eo'ld Carlo G. Alberti, Milan, Luigi Be'rnardi and Giovanni acetic solution-(5 to +5 C.).

Semmo TorineSer and Alberto e' g By means of saponification, these oxazolidones igive Milan, Italy, assignors to =So'cieta-Farmaeeutiei-Itaha, a the desired 3 (6),

summation of Italy that may be more readily isolated in form of their salts.

No Drawing. Application'betohr 18,1935 10 Sap'onifica'tion is accomplished by heating with :either Serial No.'541,532 acids or bases. Particularly efiicient for this purpose are concentrated hydrochloric acid or a boiling, saturated Chums Pnonty" apphcafion Italy October 1954 baryta solution. The saponification takes from 2 to T0 13 Claims. (Cl. 260-307) hours.

i 15 The above-described synthesis may be represented by The present invention relates to a new method of the following reactions:

' n Nit, NH H oo-NH-NH,

preparing l-aryl-Z-amino-B-alkoxypropane=1 ols, having wherein Ar represents an aryl and -R,R represent lower the general formula alkyls.

i 40 The compositions according to this invention include two centers of asymmetry and, therefore, may occur in r the form of diastereoisomcrs, the so-called threo-and Whefeln represents an 'y group and Rvfepl'eseflts a erythro-diastereoisomers, while-each of them in turn may lower alkyl group. Moreover, the invention relates to :new b Present i h dextrg-rotatoly, laevo-rotatory or intermediates obtained in the course of preparing these raeemie f on N111 p l I Except where expressly indicated, this specification Arlflamlno i yp p a 1'evamablestaltmgmafe' relates to any of these isomers and to mixtures thereof. T1318 1n P p Pharmaceutical, compounds, such The following example is furnished to illustrate, but not members of the group of aminoalcohols which includes a to E i h present invention i any manner Th number of SYmhetiS? 'composififlfls reactants set forth therein may be obviously substituted hlbitmg sympathomlmefic, pa o y anesthetic and by other reactants of similar properties without departother desirable pharmacological eifects. Recently, 'even 'i f h scope f h d d J i an antibiotic compound, chloroamphenicol (D-threo-lp-nitrophenyl-Z-dichloroacetamino-1 ,3-propanediol) has Example been added to this group. Phenylamino propanediols, 26 gr. of granular zinc to which a'sma'll'iodine crystal is such as l-phenyl-2-amino-3-methoxypropanee1eol, maybe added, are heated in a suitable flask until incipient iodine readily transformed into chloramphenicol. sublimation. A solution of gr. benzaldehyde and 69 The herein disclosed synthesis of 1-aryl-2-amino-3- gr. fi-methoxy-a-bromo-methyl .propionate in a mixture alkoxypropane-l-ols comprises condensing I an :arylof 130 cc. benzene and 40 cc. ether is then slowly added. aldehyde (1), particularly an excess of benzaldehyde, with 60 All these materials must be perfectly anhydrous. Upon an a-halo-fi-alkoxy-alkyl propionate (2 in the presence completion of the addition, a brisk reaction takes place of zinc in an anhydrous solvent such as ethyl ether or and Zn is slowly dissolved. After heating to 70 C. for benzene, or a mixture of the two, at a temperature between 45 minutes, the reaction mixture is cooled. Upon adding 0 and C. 100 gr. ice and cc. water, H 80 is carefully added rz-HaIo-fi-alkoxy-alkyl propio'nates would be expected 65 until the solution is acid against Congo paper. The to lose their alkoxy group under the influence of-thevaction benzene layer is separated and, after dehydration, is of the zinc rather than enter into a condensation with evaporated under reduced pressure. The-residue a thick the aldehyde. We made the surprising discovery, howgummy substance, is distilled in high vacuum (B. P. 144- ever, that, under the aforestated conditions, this reaction 146 C. at 3 mm. Hg residual pressure) and erythro-uis contained to such an extent that it does not interfere to 70 methoxymethyl-B-phenyl-B-methyl hydracryiate is obany substantial degree with the afore-mentioned condentained in the form of a viscous oil.

sation. To the erythro-a-methoxymethyl-rS-phenyl-fihydroxycharcoal and 'is left standing to crystallize,

' responding hydrazide obtained in thismanner hasta M. P.

methylpropionate (15 gr.),

diluted with absolute alcohol 10 cc.) are added 6 gr. of 85% hydrazine hydrate and *the mixture is heatedefor l'hour on a boiling water-bath.

The Warm solution is filtered with 0.5 gr. of decolorizing The corof 119 120 0., 7 a

8 gr. CH COOH are added to a suspension of 11 gr. of erythro-a-methoxymethyl-fl-phenyl-hydracrylic acid hydrazide in 80 cc. H and 25v gr. ice and then slowly,

- while vigorously stirring,'a solution of 7 gr. NaN0 in v20 'cc. H O. A gummy substance is obtained which, upon extraction with benzene after evaporation of the solvent, j leaves a residue that is oily at' first but, after addition of a small: amount of ether, changes to crystalline 'cis-4- methoxymethyl-S-phenyl-2 oxazolidone which, upon re- -c rys'tallization from a benzene-ether mixture, is obtained in form of small white flak'es having a M. P. of 134- 13sc. 6 gr; of this material are dissolved in 100 cc; alcohol,

500 cc. of water. Afterrefiuxing for V6 hours,;the 'mixture. is cooled and acidified with hydrochloric acid.. The

alcohol and part of thei-water rare-then distilled off in vacuum, "the mixture is made alkaline and extracted '6 times with ethylacetate (50 cc. each time), dried with sodium' sulfate and evaporated in vacuum" A yellow oil is left which does not crystallize;

Upon taking this oil, up with ether and adding an ether solution of HCl, chlorohydrate of erythro-l-phenyl-Z- amino-3-methoxypropane1 olseparates as asolid prod ucttwhich' after recrystallization'from alcohol-ether has a' M. P. of 164166 C.

We claim: a

1'; The process of preparing l aryl-2-amino-3-alkqxyfi propane- 1 015 that have the general formula 7 OH NH: 7

wherein Ar represents an aryl and R represents a lower Valkyl, said process comprising reacting an aryl aldehyde 7' with an oz-halo-fi-alkoxy alk'yl propionate in an fa'nhydrous solvent sQh ti Qn an d in thejpresenceof zine at a "t'e'mperaturefbetween0 andfl00 C., cooling, taking up with watefl'acidifyin'g jagainst Congo paper; separat ing and dehydrating the solvent layer, evaporating the solvent, distilling the residue in high vacuum, dissolving distilled a-alkoxy methyl-)3 hydroxy)S-aryl alkyl propioi: nate in anhydrous,alcohohgadding hydrazine hydrate, heating on a boiling 'water-bath, letting the solution stand, separating the, crystalline precipitate. of hydrazide 'of u-alkoxy-methyl-fihydroxy-ti-aryl-alkyl propionate, suspending in, ice water, treating in the cold with nitrous acid, extracting with a solventand evaporatingin vacuo to separate V5-aryl4-alkoxy-rnethyl-2-oxazolidone, dissolving in alcohol, refluxing for 2 to hours with a saponifying agent, and' separating the resulting l-aryl-Z- amino-3-alkoxypropane-j ol. I V V 2.=The process of preparing a-alkox'ymethyl-p-hydroxy-fl-aryl-alkyl apengort-ouion' V l on COOR V wherein Ar represents an aryl and R, R represent lower alkyls, said'process comprisingtreacting an arylaldehyde V V V V ALCHO I with an a halo-fi-alkoxy-alkyl propionate, RO.CH CHX--COOR' iwherein K'R' represent flower alkyls and X represents [a halogen, intan anhydrous solvent solution and in the V 'presence of zinc at a temperature between 0 and 100 C.,' cooling, taking up with water, acidifying against o sreper sepa n /r nd dehy the ol propionates of the general formula added 'to a solution or 18- gr. barium hydroxyde in V 7 layer, evaporating the solvent and distilling the residue in high vacuum to separate a-alkoxy-methyl-p-hydroxy- S-aryl-alkyl propionate.

3. The process according to claim 2, whereinsaid arylaldehydeis benzaldehyde, said u-halo-[i-alkoxy-alkyl V propionate is Va-bromo-fl-methoxy-methyl propionate and said solvent is a mixture of anhydrous ethyl ether and benzene.

4. The process of preparing hydrazides of'a-al koxy- I methyl-5-hydroxy-,8-aryl-alkyl propionates of the general formula V e i V ar-onon-omon l 7 on o-NH-Nm V wherein Airepresents'an aryl and R represents a lower alkyl, said process comprising reacting an aryla ldehyde with an a-halo fi-alkoxy -alkyl propionate in an anhydrous solvent solution and in the presence of zinc at a temperature between 0 and 100 C,, cooling, taking up with water, acidifying against Congo paper,,separating f and dehydrating the solvent layer, evaporating the sol- 3 vent, distilling the residue in high vacuum, dissolving .oxazolidones of the general formula distilled ct-alkoxy-methyl-p3-hydroxy-p3-aryl-alkyl propionate in anhydrous alcohol, adding hydrazine hydrate, heating on a boiling water-bath, filtering hotwith decolorizing charcoal, letting the filtrate stand and separatdrous solvent solution and in the presence of zinc at a temperature betWeeriLO" and 100 ,C., cooling, taking up with water, acidifying against Congo paper, separating and dehydrating the solvent layer, evaporating the "solvent in vacuum, distilling the residue in high vacuum, 7

dissolving distilled a-alkoxy-methyl-fi-hydroxy-B-arylalkyl propionate in anhydrous alcohol, adding hydrazine, hydrate, heating on a boiling water-bath, filtering hot- V with decolorizing charcoal, letting the filtrate stand; separating the crystallineprecipitate of hydrazide of q-alkoxymethyl-/8 hydroxy-B-aryl-alkyl propionate, suspending in ice water, adding acetic acid, treating with an aqueous sodium nitrate sol ution in. the cold, separatingthe resulting gummy substance, extracting with benzene, adding a 7V small amount of ether to the oily residue,*dissolving the resulting crystalline'r'naterial in a benzene-ether' mixture e and recrystallizing yl-2-oxazolidone.

fied ether andseparating a solid and separating -5 aryl-4-alkoxy-methv 6. The process of preparing l-aryl-2 -amino -3i-talkoxypropane-l-ols according to claim 1, comprising'dissolv- 'ing said 5-aryl-4-alkoxy;rnethyl-2-oxazolidone in ethanol,

adding an (about 3%) aqueous solution ofjbarium hydroxide, refluxing for 2, to 10"hours, cooling, acidifying with hydrochloricacid, evaporating the alcohol and'part got the water in vacuum; making alkaline, eXtracting're-' peatedly with ethyl acetate,- drying, taking up with acidiformula V V V V V V V Ar-crt eH-omort wherein Y represents an acid residue. 1

Compounds of the general formula sharpen- 011,01:

wherein Ar represents phenyl, R represents a lower' alk yl,

product of the general A represents a hydroxyl, Z represents a member of the group consisting of COOR and --CONH--NH and A plus Z represent OCONH.

8. Compounds of the general formula Ar-CH-OH-CHzOR wherein Ar represents phenyl and R, R' represent a lower alkyl.

9. Erythro-a-methoxymethyl p phenyl-B-methylhydracrylate.

10. Compounds of the general formula ArCH-OH-CH:OR

(5H CONH-NH: wherein Ar represents phenyl and R represents a lower alkyl.

11. Erythro a methoxymethyl ,8 phenylhydracrylic acid and hydrazide.

12. Compounds of the general formula Ar-CH-CHCH=OR wherein Ar represents phenyl and R represents a lower alk 1.

1 3. Cis-4-methoxymethyl-S-phenyl-2-oxazolidone.

References Cited in the file of this patent UNITED STATES PATENTS 2,399,118 Homeyer Apr. 23, 1946 2,513,346 Moersch et a1. July 4, 1950 FOREIGN PATENTS 913,163 France May 20, 1946 858,402 Germany Dec. 8, 1952 

1. THE PROCESS OF PREPARING 1-ARYL-2-AMINO-3-ALKOXYPROPANE-1-OLS THAT HAVE THE GENERAL FORMULA 